Membrane assembly of Shiga toxin glycosphingolipid receptors and toxin refractiveness of MDCK II epithelial cells

Legros, Nadine; Pohlentz, Gottfried; Steil, Daniel; Kouzel, Ivan U.; Liashkovich, Ivan; Mellmann, Alexander; Karch, Helge; Müthing, Johannes

doi:10.1194/jlr.m083048

Cited by 11 publications

(18 citation statements)

References 132 publications

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“…Remarkably, the swine-pathogenic Stx2e is special among the various Stx subtypes showing, besides binding toward Gb3Cer, a pronounced preference toward Gb4Cer carrying the GalNAcβ1–3Galα1–4Galβ1–4Glc tetrasaccharide [ 316 , 318 , 319 ] and a promiscuous binding activity toward elongated Gb4Cer structures. These are globopentaosylceramide (Gb5Cer) with Galβ1–3GalNAcβ1–3Galα1–4Galβ1–4Glcβ1–1Cer structure [ 320 ] and GalNAcα1–3GalNAcβ1–3Galα1–4Galβ1–4Glcβ1–1Cer, which is defined as the Forssman GSL [ 316 , 321 ]. A Gb3 analogue trisaccharide was found to bind to the 3 densely located binding sites of each of the identical B subunits, whereby all 15 trisaccharide molecules bind to one side of the B pentamer, indicating that this side faces the cell membrane [ 290 , 291 , 322 , 323 , 324 ].…”

Section: Ehec-caused Diseases and Damage Of Human Target Cellsmentioning

confidence: 99%

Valid Presumption of Shiga Toxin-Mediated Damage of Developing Erythrocytes in EHEC-Associated Hemolytic Uremic Syndrome

Detzner

Pohlentz

Müthing

2020

Toxins

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The global emergence of clinical diseases caused by enterohemorrhagic Escherichia coli (EHEC) is an issue of great concern. EHEC release Shiga toxins (Stxs) as their key virulence factors, and investigations on the cell-damaging mechanisms toward target cells are inevitable for the development of novel mitigation strategies. Stx-mediated hemolytic uremic syndrome (HUS), characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal injury, is the most severe outcome of an EHEC infection. Hemolytic anemia during HUS is defined as the loss of erythrocytes by mechanical disruption when passing through narrowed microvessels. The formation of thrombi in the microvasculature is considered an indirect effect of Stx-mediated injury mainly of the renal microvascular endothelial cells, resulting in obstructions of vessels. In this review, we summarize and discuss recent data providing evidence that HUS-associated hemolytic anemia may arise not only from intravascular rupture of erythrocytes, but also from the extravascular impairment of erythropoiesis, the development of red blood cells in the bone marrow, via direct Stx-mediated damage of maturing erythrocytes, leading to “non-hemolytic” anemia.

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Section: Ehec-caused Diseases and Damage Of Human Target Cellsmentioning

confidence: 99%

Valid Presumption of Shiga Toxin-Mediated Damage of Developing Erythrocytes in EHEC-Associated Hemolytic Uremic Syndrome

Detzner

Pohlentz

Müthing

2020

Toxins

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“…2 ). Once at ER, the A1 fragment of the bacterial toxin (upon cleavage) exerts its ribotoxic effect resulting in the inhibition of protein biosynthesis followed by cell death (Legros et al 2018 ). The precise molecular mechanism involves a complex interaction of the bacterial effector molecules and host lipids that manipulates the host signaling networks, such as apoptotic pathways (Karpman et al 1998 ; Clements et al 2012 ; Burlaka et al 2013 ).…”

Section: Lipids In Bacterial Infectionsmentioning

confidence: 99%

“…Gb 3 receptors belong to a diverse group of Glycosphingolipids (GSLs), which along with cholesterol and sphingomyelin, regulate the stabilization and spatial organization of PM microdomains. Recently, Legros et al ( 2018 ) carried out a comprehensive study on the composition of Stx-binding glycosphingolipids (GSLs) in Madin-Darby canine kidney (MDCK) II epithelial cells. They demonstrated that the distribution of GSLs was limited to the detergent-resistant membranes (DRMs), while ascertaining the lipid composition of DRM and non-DRM preparations.…”

Section: Lipids In Bacterial Infectionsmentioning

confidence: 99%

Various Facets of Pathogenic Lipids in Infectious Diseases: Exploring Virulent Lipid-Host Interactome and Their Druggability

Dadhich

Kapoor

2020

J Membrane Biol

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Lipids form an integral, structural, and functional part of all life forms. They play a significant role in various cellular processes such as membrane fusion, fission, endocytosis, protein trafficking, and protein functions. Interestingly, recent studies have revealed their more impactful and critical involvement in infectious diseases, starting with the manipulation of the host membrane to facilitate pathogenic entry. Thereafter, pathogens recruit specific host lipids for the maintenance of favorable intracellular niche to augment their survival and proliferation. In this review, we showcase the lipid-mediated host pathogen interplay in context of life-threatening viral and bacterial diseases including the recent SARS-CoV-2 infection. We evaluate the emergent lipid-centric approaches adopted by these pathogens, while delineating the alterations in the composition and organization of the cell membrane within the host, as well as the pathogen. Lastly, crucial nexus points in their interaction landscape for therapeutic interventions are identified.

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“…The toxin subtypes have recently been shown to have different receptor binding preferences [46,47]. For example, Stx1a preferentially binds Gb3 with detectable binding to globotetraosylceramide (Gb4), while Stx2a shows a strong preference for Gb3 and marginal binding to Gb4.…”

Section: The Toxinsmentioning

confidence: 99%

“…Toxin subtype Stx2e displays a more promiscuous pattern of glycolipid binding, with preferential binding to Gb4, but also binding Gb3, pentahexosylceramides with Gb4-elongated core structures, including Forssman glycosphingolipid, and globopentaosylceramide (Gb5) [48,49]. Legros and colleagues [47] characterized the Stx-binding glycolipids expressed in detergent-resistant membrane preparations from Madin-Darby canine kidney (MDCK) II epithelial cells. The Stx1a-, Stx2a- and Stx2e-binding glycolipids Gb3 and Gb4, and the Stx2e-binding Forssman glycosphingolipid, were expressed by the cells.…”

Section: The Toxinsmentioning

confidence: 99%

Roles of Shiga Toxins in Immunopathology

Lee

Tesh

2019

Toxins

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Shigella species and Shiga toxin-producing Escherichia coli (STEC) are agents of bloody diarrhea that may progress to potentially lethal complications such as diarrhea-associated hemolytic uremic syndrome (D+HUS) and neurological disorders. The bacteria share the ability to produce virulence factors called Shiga toxins (Stxs). Research over the past two decades has identified Stxs as multifunctional toxins capable of inducing cell stress responses in addition to their canonical ribotoxic function inhibiting protein synthesis. Notably, Stxs are not only potent inducers of cell death, but also activate innate immune responses that may lead to inflammation, and these effects may increase the severity of organ injury in patients infected with Stx-producing bacteria. In the intestines, kidneys, and central nervous system, excessive or uncontrolled host innate and cellular immune responses triggered by Stxs may result in sensitization of cells to toxin mediated damage, leading to immunopathology and increased morbidity and mortality in animal models (including primates) and human patients. Here, we review studies describing Stx-induced innate immune responses that may be associated with tissue damage, inflammation, and complement activation. We speculate on how these processes may contribute to immunopathological responses to the toxins.

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Membrane assembly of Shiga toxin glycosphingolipid receptors and toxin refractiveness of MDCK II epithelial cells

Cited by 11 publications

References 132 publications

Valid Presumption of Shiga Toxin-Mediated Damage of Developing Erythrocytes in EHEC-Associated Hemolytic Uremic Syndrome

Valid Presumption of Shiga Toxin-Mediated Damage of Developing Erythrocytes in EHEC-Associated Hemolytic Uremic Syndrome

Various Facets of Pathogenic Lipids in Infectious Diseases: Exploring Virulent Lipid-Host Interactome and Their Druggability

Roles of Shiga Toxins in Immunopathology

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